PROJECT SUMMARY/ ABSTRACT Children and adolescents often grow up in the face of substantial developmental stress (i.e. trauma). While for some, this shifts the developmental trajectory to that of mental and general health disorders, others are resilient. Most research on developmental psychopathology is focused on risk while little is known on the mechanisms that confer resilience. The current study aims to identify biological (genomic, immune), psychological and cognitive mechanisms that underpin resilience in youth as defined by having low mood- anxiety and suicidal outcomes in youth with substantial developmental stress exposure (i.e. trauma and family history of depression). Elucidating resilience mechanisms has huge clinical implications as it will improve stratification of risk to develop depression and/or suicidal behavior, and could identify biological, psychological and cognitive targets that can inform development of future preventive interventions aimed at promoting resilience, reducing the mental and general health adverse outcomes associated with childhood adversity. The study capitalizes on a large dataset of genotyped youths from the Philadelphia Neurodevelopmental Cohort (PNC), that have been comprehensively phenotyped for cognitive performance and psychopathology, and that reported substantial trauma exposure. The proposed research integrates genomic and cognitive data with clinical measures used to define resilience in cross sectional analysis of ~9500 PNC youths (Aim 1); incorporates longitudinal data of depression and suicide measures, pulled from electronic medical record in a subset of ~750 PNC youths (Aim 2); and relies on prospective data collection that includes immune profiling of selected PNC individuals to allow identification of immune signature of resilience (Aim 3). Integration of genomic with clinical, cognitive and immune data will allow predictive modeling, and Big Data driven analysis will allow identification of resilience mechanisms. The candidate is a Child and Adolescent Psychiatrist physician scientist who is committed to translational research in youth at risk for psychiatric conditions. His overarching career goal is to develop methods for early identification of subclinical phenotypes before the onset of major psychiatric disorders (i.e. depression and suicide attempts) and, through neuroscience informed interventions, divert the developmental trajectory from that of risk to that of resilience. The career development plan capitalizes on a multidisciplinary mentorship team. It involves one-on one mentoring with the primary ?clinical research? mentor as well as the genomic, biostatistical, neurocognitive and immune system expert co- mentors, integrated with hands on research supervision in data collection and statistical analysis, and didactic coursework and workshops. The program is tailored to meet research and training aims. The project will be conducted in the fostering environment of the Children?s Hospital of Philadelphia and the University of Pennsylvania, that will provide the academic mentorship and the required resources to execute the research and training aims, allowing the candidate to launch an independent research career.